Project Details
Projekt
Identification and characterization of ciliary WNT inhibitors to improve RPE maturation and function
Applicant
Professorin Helen May-Simera, Ph.D.
Subject Area
Cell Biology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 498244102
The vertebrate eye is a complex organ, consisting of multiple cell-types with many specialized functions. Defects in any one of these cell-types result in various eye diseases, often leading to vision impairment and, ultimately, blindness. A multitude of retinal diseases have genetic causes and are hereditary. Strikingly, at least 50 % of these encode genes associated with the primary cilium, a microtubule-based signaling organelle found on the surface of most vertebrate cells. The retinal pigment epithelium (RPE) is a ciliated monolayer epithelium that supports the retina and is essential for visual transduction. In the last years our lab has focused on the role of primary cilia in the RPE in coordinating development and function which is largely regulated via regulation of WNT signaling. We have also been able show that ciliary dysfunction in the RPE significantly contributes to retinal degeneration.Despite the high percentage of genes linked to retinal degeneration encoding ciliary associated proteins, the development of treatment options is currently limited with the few approaches being developed relying on gene replacement predominantly in photoreceptor cells. Considering our findings on the vital role of the cilium in the RPE contributing to disease pathogenesis, it is essential to also focus on this cell type. Our long-term goal is to identify cell-based therapies to counteract neuroretinal degeneration in patients with cilia related ocular disorders with a particular focus on the RPE. Since our published and preliminary data show WNT signaling defects during RPE maturation in ciliopathy models, and improved iPSC-RPE maturation upon pharmacological inhibition of WNT, our objective in this application is to identify novel, more specific WNT inhibitors, which will be tested in comparison to known WNT inhibitors on their ability to rescue impaired cilia deficiencies and improve maturation and function of iPSC-RPE. Our central hypothesis is that we can accelerate and improve RPE maturation not only in control but also in diseased states via pharmacological manipulation of ciliary mediated WNT signaling. As many of the currently known compounds are less specific, leading to off target side effects and toxicity, there is a critical need to identify RPE specific WNT inhibitors that could be used to design treatment strategies. Moreover, pharmacologically manipulation of (ciliary) WNT signaling provides us with insights into RPE related signaling pathways. Not only can this be off benefit to visual community optimizing iPSC-RPE differentiation and maturation, but it could also enable us to provide individual treatment strategies for example in the case of ciliary related retinal degeneration.
DFG Programme
Priority Programmes
